1. Field of the Invention
The present invention relates to a process for preparing quinolonecarboxylate derivatives, which are useful as an intermediate for the preparation of quinolone anti-bacterial agents.
2. Description of the Related Art
Quinolonecarboxylate derivatives are useful as an intermediate for the preparation of various quinolone anti-bacterial agents, including sparfloxacin, gemifloxacin, trovafloxacin, ciprofloxacin, temafloxacin, fleroxacin, and levofloxacin.
Conventional processes for preparing quinolonecarboxylate derivatives includes a quinoline-ring forming step (i.e., cyclization step), which is performed in the presence of a base such as potassium carbonate or sodium hydride (see U.S. Pat. No. 5,639,886; J. Med. Chem., 1989, 32,1313–1318; WO 00/50428; U.S. Pat. No. 4,795,751; JP Publication No. 89/100165; U.S. Pat. No. 4,730,000; J. Med. Chem., 1986, 29, 2363–2369; and U.S. Pat. No. 4,777,253).
Potassium carbonate is commercially available in form of granules. However, when granular potassium carbonate is used in a reaction for cyclizing a quinoline-ring, the reaction cannot be completed and the yield is very low, about 20˜30%. Therefore, in order to complete the reaction, granular forms of potassium carbonate need to be reduced to powder, which requires an additional process, excess amounts of potassium carbonate (about 3–5 eq.), and/or equipment for grinding the granules in a reactor. Further, when a reaction is performed in high temperature using potassium carbonate, carbon dioxide (CO2) gas is produced, which makes the process dangerous. Accordingly, potassium carbonate has difficulties to be applied to an industrial-scale mass production.
Meanwhile, sodium hydride is very sensitive to water, which makes the reaction violent and dangerous (e.g., a possibility of explosion). Further, the yield thereof shows very high variation, about from 50 to 90%, so that it is also difficult to be applied to an industrial-scale mass production.